The broad objective of the research described in this proposal is to define and clarify those factors which operate in the interaction of radiation and drugs in mammalian cells in culture. A major portion of the work will be devoted to the influence of the development of drug resistance on several radiation response parameters. Drug resistance is defined as a decrease in sensitivity to the agent as measured by cell survival studies. The radiation responses to be measured include radiation survival, capacity to repair sublethal and potentially lethal radiation injury, the sedimentation behavior of DNA from irradiated cells in alkaline sucrose density gradients, the effect of radiation on drug uptake, and a systematic examination of cross-resistance between chemotherapeutic agents. Chinese hamster lung fibroblasts (V-79) cells will be used exclusively in these studies. Intracellular concentrations of drug will be determined flourometrically for those agents which have a chromophore as part of their chemical structure. The kinetics of drug uptake and release by whole cells relative to total drug concentration and drug bound to DNA will be determined. To gain further insight into the development of drug resistance, and the response of resistant cells to radiation, synchronous cell studies will be accomplished with respect to drug uptake, cell survival, and radiation response. It is hoped that the information derived from these studies will provide insight into the possible mechanisms by which tumor cells develop resistance to chemotherapeutic agents, which may lead to relapse, how such cells may respond to radiation, and the appropriate choice of alternative chemotherapeutic agents.